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Phase 2 Study of MEDI4736 in Patients With Glioblastoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2016 by Ludwig Institute for Cancer Research
Sponsor:
Collaborators:
MedImmune LLC
Cancer Research Institute, New York City
Cure Brain Cancer Foundation, Australia
Information provided by (Responsible Party):
Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier:
NCT02336165
First received: December 23, 2014
Last updated: June 16, 2016
Last verified: June 2016
  Purpose

This is an open-label, non-randomized, multicenter Phase 2 study of MEDI4736 with three non-comparative cohorts:

Cohort A: 37 subjects with newly diagnosed unmethylated MGMT GBM will receive MEDI4736 every 2 weeks in combination with standard radiotherapy.

Cohort B: 30 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks as monotherapy.

Cohort B2: 32 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks + bevacizumab every 2 weeks (10 mg/kg).

Cohort B3: 32 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks + bevacizumab every 2 weeks (3 mg/kg).

Cohort C: 17 bevacizumab-refractory subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with continued bevacizumab.


Condition Intervention Phase
Glioblastoma
Drug: MEDI4736
Radiation: Radiotherapy
Biological: Bevacizumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 2 Study to Evaluate the Clinical Efficacy and Safety of MEDI4736 in Patients With Glioblastoma (GBM)

Resource links provided by NLM:


Further study details as provided by Ludwig Institute for Cancer Research:

Primary Outcome Measures:
  • Clinical Efficacy, as judged by survival, is the primary objective of the study for all cohorts but the primary endpoints differ by cohort due to the difference in patient populations. [ Time Frame: 6-12 months ] [ Designated as safety issue: No ]

    In Cohort A, the primary endpoint is the Overall Survival (OS) rate at 12 months.

    In Cohort B, the primary endpoint is the percentage of subjects who remain progression free at 6 months (PFS-6)

    In Cohort B2 and B3, the primary endpoint is the percentage of subjects who remain progression free at 6 months (PFS-6).

    In Cohort C, the primary endpoint is the Overall Survival (OS) rate at 6 months.



Secondary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: up to 15 months ] [ Designated as safety issue: Yes ]
    Subjects are evaluated on an ongoing basis while they are on study to evaluate any toxicities or side effects they may experience due to study treatment. These may be identified by lab tests, physical exam or other methods.

  • Evaluation of Clinical Efficacy by median Progression-Free Survival, and Overall Survival as well as overall response rate (ORR). [ Time Frame: up to 36 months ] [ Designated as safety issue: No ]

    Progression-free survival will be defined as the number of days from the date of first dose to the date of earliest disease progression.

    Overall survival (OS) will be measured for each subject with time origin at the date of study day 1 until recorded date of death or last follow-up.

    Overall response rate (ORR) will be assessed by modified RANO criteria.


  • Pharmacokinetic profile of MEDI4736, including half-life, Tmax, Cmax and other parameters. [ Time Frame: up to 15 months ] [ Designated as safety issue: No ]
    Samples for pharmacokinetic (PK) assessments will be collected based on the protocol schedule while the subject is on study.

  • Quality of Life (EORTC QLQ-30/BN20). [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
    Health related quality of life (HRQoL) will be self-reported and measured with the use of the validated core quality of life questionnaire (QLQ-C30) and a quality of life questionnaire specifically for subjects with brain tumors (BN-20) of the European Organization for Research and Treatment of Cancer in each treatment cohort.


Other Outcome Measures:
  • Evaluation of patient neurologic function (NANO scale). [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]

    Neurologic function of patients in each treatment cohort will be assessed using The Neurologic Assessment in Neuro-Oncology (NANO) Scale: A Tool To Assess Neurologic Function for Integration in the Radiologic Assessment in Neuro-Oncology (RANO) Criteria.

    The NANO scale is an objective and quantifiable metric of neurologic function that incorporates direct observation/testing of eight relevant neurologic domains designed to be evaluated quickly during a routine clinic visit. The NANO scale is designed to complement subjective, patient-reported outcomes such as health-related quality of life questionnaires.

    For this study, the NANO scale will not be used to define clinical progression. Changes in level of function scores for each neurologic domain defined by the NANO scale will be descriptively summarized on an individual patient basis over time. For each cohort, the median survival of patients with and without significant neurologic decline as defined by the NANO scale.


  • MEDI4736 biological activity as assessed by immunologic markers. [ Time Frame: up to 15 months ] [ Designated as safety issue: No ]

    Samples for exploratory pharmacodynamic assessments will be collected according to the schedule of assessments presented in the protocol.

    Subjects who received at least one dose of MEDI4736, and provide baseline and at least one post-treatment sample (if applicable), will be evaluated. Results from these assessments will be evaluated in relation to outcome. Descriptive statistics will be used to summarize these measurements.



Estimated Enrollment: 108
Study Start Date: February 2015
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A
Approximately 37 subjects with newly diagnosed unmethylated MGMT GBM will receive MEDI4736 every 2 weeks in combination with standard radiotherapy.
Drug: MEDI4736
Anti-PD-L1
Other Name: Durvalumab
Radiation: Radiotherapy
Experimental: Cohort B
Approximately 30 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks as monotherapy.
Drug: MEDI4736
Anti-PD-L1
Other Name: Durvalumab
Experimental: Cohort C
Approximately 17 bevacizumab-refractory subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with continued bevacizumab.
Drug: MEDI4736
Anti-PD-L1
Other Name: Durvalumab
Biological: Bevacizumab
Other Name: Avastin
Experimental: Cohort B2
Approximately 32 bevacizumab-naive subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with bevacizumab (10 mg/kg).
Drug: MEDI4736
Anti-PD-L1
Other Name: Durvalumab
Biological: Bevacizumab
Other Name: Avastin
Experimental: Cohort B3
Approximately 32 bevacizumab-naive subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with bevacizumab (3 mg/kg).
Drug: MEDI4736
Anti-PD-L1
Other Name: Durvalumab
Biological: Bevacizumab
Other Name: Avastin

Detailed Description:

Under some circumstances, the immune system may control or even eliminate tumors. MEDI4736 is an experimental antibody that is made in the laboratory. Antibodies stimulating the immune system have been developed for treatment of human cancers. The idea behind developing this type of experimental drug is that stimulating the immune system could be a different way of preventing cancer growth or killing cancer cells.

This study will also evaluate how much MEDI4736 is in the blood at various times, whether the immune system becomes activated following treatment and the effect of treatment on cancer.

In subjects with newly diagnosed GBM (Cohort A), MEDI4736 will be administered with standard treatment which includes radiation following surgery. The idea to add MEDI4736 to standard radiation is that the radiation will cause cell death and release tumor proteins which will increase the immune activity of MEDI4736.

Subjects with recurrent GBM and who have never been treated with Avastin (Cohort B), will receive MEDI4736 alone.

In Cohorts B2 and B3, subjects with recurrent GBM and who have never been treated with Avastin will receive MEDI2736 in combination with standard or low dose Avastin respectively.

Subjects with recurrent GBM and who have currently progressed on Avastin (Cohort C), will continue receiving Avastin in combination with MEDI4736. Avastin is another type of antibody that prevents the growth of blood vessels that feed the tumor. Despite Avastin being approved by the FDA for cancer based on tumor response, essentially all patients eventually progress due to resistance.

The idea to treat cancer with MEDI4736, with or without Avastin, is to identify alternative treatment options for cancer, by stimulating the immune system to prevent cancer growth.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Cohort A:

  1. Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for standard radiation therapy.

    Cohorts B, B2, B3 and C:

  2. First or second recurrence of GBM by diagnostic biopsy or contrast enhanced MRI per modified RANO criteria (122), with last baseline MRI confirmation within 14 days prior to Study Day 1.

    NOTE: Recurrence is defined as progression following therapy (i.e., chemotherapy; radiation). If the subject had a surgical resection for relapsed disease and no anti-tumor therapy was administered for up to 12 weeks, and the subject has further evidence of tumor growth or undergoes another resection, this will be considered as one episode of recurrence.

  3. On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease outside of the radiation field or histopathologic confirmation of unequivocal tumor).
  4. Cohort B, B2, B3: No prior VEGF/VEGFR targeted therapy; Cohort C: No more than one prior bevacizumab regimen.
  5. Recovery from any prior treatment clinically significant, related adverse events to grade ≤ 1 or pretreatment baseline with the exception of alopecia and laboratory values listed per inclusion criteria.

    Cohorts A, B, B2, B3 and C:

  6. Subjects with measurable or non-measurable disease.
  7. Histopathologic confirmation of glioblastoma.
  8. At the time of Study Day 1, subjects must be at least 4 weeks since major surgical procedure, open biopsy, or significant traumatic injury; there should be no anticipation of need for major surgical procedure during the course of the study.

    There should be no core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Study Day 1.

  9. Subjects who have previously been treated with the Optune device are eligible for the study as long as toxicity related to the treatment has resolved to ≤ Grade 1 or baseline.
  10. ECOG ≤ 1 or Karnofsky performance status of ≥ 70.
  11. Adequate hematologic, renal and hepatic function, as defined below:

    • Absolute Neutrophil Count ≥ 1000/mm3
    • Platelet count ≥ 100,000/mm3
    • Total bilirubin ≤ 1.5 x ULN; or if subject has Gilbert syndrome, then total bilirubin ≤ 3 x ULN
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN
    • Creatinine ≤ 1.5x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula):

      • Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum creatinine in mg/dL
      • Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL Cohorts B2, B3 and C
    • Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample.
  12. Age must be greater than or equal to 18 years at date of consent.
  13. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the USA) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.

Exclusion Criteria:

All Cohorts

  1. Primary tumors localized to the brainstem or spinal cord.
  2. Locally directed therapies including but not limited to stereotactic radiosurgery, re-irradiation, Gliadel, and therapeutics administered by direct injection or convection-enhanced delivery within 6 months of start of study treatment.
  3. Prior exposure to MEDI4736 or other anti-PD-1, anti-PD-L1, anti-CTLA4 antibodies.
  4. Presence of diffuse leptomeningeal disease or extracranial disease.
  5. Active, suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and Hashimoto's thyroiditis). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  6. Known primary immunodeficiency or active HIV.
  7. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or hepatitis C virus ribonucleic acid (HCV antibody).
  8. History of organ transplant requiring use of immunosuppressive medication.
  9. History of active tuberculosis.
  10. Significant active systemic illness including infections requiring intravenous antibiotics.
  11. Current pneumonitis or interstitial lung disease.
  12. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only.
  13. History of severe allergic reactions to any unknown allergens or any components of the study drugs.
  14. Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.
  15. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
  16. Lack of availability for follow-up assessments.
  17. Lack of availability for Post Study Follow-up contacts to determine relapse and survival.
  18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
  19. Women of childbearing potential not using a medically acceptable means of contraception for the duration of the study and unsterilized males not willing to abide by requirements for contraception as stated in Section 5.4.
  20. If a subject previously received another investigational treatment, the last dose of investigational treatment was administered within 4 weeks of Day 1 of the study.
  21. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk.
  22. Cohorts B2, B3 and C:

    • Evidence of hemorrhage on the baseline MRI or CT scan other than those that are ≤ grade 1 and either post-operative or stable on at least two consecutive scans
    • Current use of warfarin sodium or any other Coumadin-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least seven days prior to starting study drug. Low molecular weight heparin and Factor Xa antagonists are allowed
    • History of clinically significant bleeding within 6 months of enrollment
    • History of arterial thromboembolism within 12 months prior to enrollment
    • Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications)
    • Any prior history of hypertensive crisis or hypertensive encephalopathy
    • Clinically significant cardiovascular disease within 12 months prior to enrollment (or randomization), including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
    • Evidence of bleeding diathesis or coagulopathy
    • History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 6 months prior to study enrollment
    • Serious, non healing wound, ulcer, or bone fracture
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02336165

Contacts
Contact: Andrew Park, PharmD 212-450-1515 clintrialinformation@licr.org

Locations
United States, California
Research Facility Recruiting
Los Angeles, California, United States, 90095
Research Facility Recruiting
San Francisco, California, United States, 94143
United States, Maryland
Research Facility Recruiting
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Research Facility Recruiting
Boston, Massachusetts, United States, 02114
Research Facility Recruiting
Boston, Massachusetts, United States, 02215
United States, Missouri
Research Facility Recruiting
St. Louis, Missouri, United States, 63110
United States, New York
Research Facility Recruiting
New York, New York, United States, 10065
Australia
Research Facility Recruiting
Melbourne, Australia
Sponsors and Collaborators
Ludwig Institute for Cancer Research
MedImmune LLC
Cancer Research Institute, New York City
Cure Brain Cancer Foundation, Australia
Investigators
Study Chair: David A. Reardon, MD Dana-Farber Cancer Institute
  More Information

Responsible Party: Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT02336165     History of Changes
Other Study ID Numbers: LUD2013-006 
Study First Received: December 23, 2014
Last Updated: June 16, 2016
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Ludwig Institute for Cancer Research:
Glioblastoma
Immunotherapy
T Cell
PD-L1
MEDI4736
Radiation
Radiotherapy
GBM

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors

ClinicalTrials.gov processed this record on December 09, 2016